Jasmonates are a family of plant stress hormones, which are released in instances of extreme UV radiation, osmotic shock, heat shock, pathogen attack and the like, to initiate various cascades. The use of jasmonates for the treatment of mammalian cancer has been disclosed in International Patent Application WO 02/080890 and in U.S. Pat. No. 6,469,061 wherein the jasmonates were shown to induce direct cytotoxicity for various types of human cancer cells derived from breast, prostate, skin, and blood cancers. Methyl jasmonate was shown to be effective in preventing development of lymphomas in mice (Fingrut and Flescher, Leukemia, 16: 608-616, 2002).
International Patent Application WO 2005/054172 discloses halogenated jasmonate derivatives, pharmaceutical compositions comprising the derivatives, and their use in reducing cancer cell growth and in treating cancer.
International Patent Applications WO 2007/066336 and WO 2007/066337 disclose jasmonate derivatives, pharmaceutical compositions comprising same, and use thereof in reducing cancer cell growth and the treatment of cancer.
International Patent Application WO 2008/111088 discloses an assay for identifying anti-cancer candidate drug molecules by comparing the activity of the candidate drug molecule with the activity of a jasmonate derivative known as having anti-cancer effect in at least one of the following: dissociating hexokinase from mitochondria, interfering with hexokinase binding to a voltage dependent anion channel, and binding to hexokinase directly.
Kniazhanski et al. (Cancer Letters, 271(1): 34-46, 2008) discloses that methyl jasmonate is cytotoxic to a range of cervical cancer cell lines. Reischer et al. (Br J. Pharmacol., 150(6): 738-749, 2007) discloses that methyl jasmonate suppresses cell motility and inhibits the development of lung metastases in metastatic melanoma cells.
Wang et al. (Society for Investigative Dermatology, 86th annual meeting: abstract ID 861, 2007) discloses that jasmonic acid and methyl jasmonate are potential agents against UVB-induced skin cancer but have low toxicity on the malignant keratinocytes A431 cell line.
US Patent Application No. US 2003/0224024 discloses compositions of jasmonate esters, including methyl jasmonate, in the form of any cosmetic composition, including compositions for treating certain diseases of the skin, such as psoriasis. US Patent Application No. US 2010/0069497 discloses use of hydroxy jasmonate derivatives for treating psoriasis.
US Patent Application No. US 2009/0197939 discloses topical use of aromatic skin active ingredients, including methyl dihydro jasmonate for cosmetic applications, including treating skin disorders, such as seborrheic dermatitis, keratosis, psoriasis.
US Patent Application No. US 2007/0082852 relates to use of jasmonic acid for inducing proliferation of fibroblasts or keratinocytes thereby formation of new skin and gum tissues, facilitate wound healing, and ameliorate the effects of aging. It is explained that signs of aging may result from processes that include keratoses.
Skin benign hyperproliferative disorders arise from abnormal growth and differentiation of epidermal cells and may be attributed to lack of response or inappropriate response to regulating factors, or alternatively to dysfunctional regulating factors. This abnormality may develop into various benign skin disorders including, ichthyiosis, seborrhea and actinic keratoses.
Keratosis is defined as any horny growth of the skin including such growths as a wart or callous. Actinic keratosis typically is a sharply outlined verrucous or keratotic growth which may become malignant. It usually occurs in the middle aged or the elderly and is due to excessive exposure to the sun.
Actinic keratoses are potentially premalignant flat keratotic lesions considered to be either carcinoma in-situ or squamous intraepidermal neoplasia. Actinic keratoses are usually induced by ultraviolet (UV) radiation, typically from sunlight and are considered to be the most important manifestation of sun-induced skin damage. Actinic keratoses are characterized by alteration of maturation of keratinocytes from the basal layer of stratum corneum as viewed in microscopic examinations. The basal cells are enlarged, the nuclei are pleomorphic and some nuclei have nucleoli. These atypical cells replace part of or the entire thickness of epidermis (Histology: from normal microanatomy to pathology, Amenta et al. (Eds.), 7th Edition, PICCIN, 1997). Untreated actinic keratoses may develop into basal cell carcinoma or squamous cell carcinoma.
Traditional treatments of actinic keratoses include the use of nonsteroidal anti-inflammatory drugs (e.g. diclofenac), immune response modifiers (e.g. imiquimod), cryosurgery, photodynamic therapy, electrocautery and chemotherapy agents, all of which are accompanied by undesirable side effects.
Hence, there is an unmet need for more potent compounds useful for treating benign hyperproliferative skin disorders with reduced side effects.